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Prasad R. Padala, MD, MS, FACHE Associate Director for Clinical Programs VISN 16/CAVHS Geriatric Research Education and Clinical Center (GRECC) Associate Professor of Psychiatry and Geriatrics, UAMS Slide 2 Disclosure of Conflict None All medication use discussed in this presentation is off-label Slide 3 Goals and Objectives By the end of the conference audience will learn: Discuss the prevalence of dementia Review the impact of dementia Discuss modifiable mid-life risk factors for dementia Discuss current evidence on strategies to prevent dementia Slide 4 Prevalence of dementia 24.3 million worldwide in 2001 81.1 million by 2040 and doubling every 20 years For people over age 60 2.6% Africa 4% Asia 6.2% Europe 6.9% North America 4 Slide 5 AD > 5 million Americans with AD 6 th leading cause of death In 2012, 15.4 million caregivers provided more than 17.5 billion hours of unpaid care ( $216 billion) In 2013, Alzheimer's will cost the nation $203 billion $1.2 trillion by 2050 5 Slide 6 How do you diagnose Clinical Multi-disciplinary teams: Memory clinics Detailed neuropsych testing Detailed medical history and physical Detailed behavioral assessments Detailed social work and pharmacy assessment Labs Neuro-imaging Slide 7 Natural history to differentiate types Case 1: 87 year old white male presenting with 10 years history Gradual onset STM > LTM On probing: Loss of smell about 10 years ago Repetitiousness, misplacing items, progressively needing more help with ADL Case 2: 76 year old AA male Sudden onset of memory problems on 7/7/2003 Went to the ER and found out that he had a stroke Was fine for two years and had another dip in memory in 2005 after TIA Case 3: 69 year old WM. Multiple altercations for insensitive comments. Recently made an inappropriate sexual comment on wifes friend Family regarding his memory Seems just fine. Waxing and waning. Frontal release signs on exam Slide 8 Neuropathologic Changes Characteristic of Alzheimers Disease Normal AP = amyloid plaques. NFT = neurofibrillary tangles. Courtesy of Albert Enz, PhD, Novartis Pharmaceuticals Corporation. AD AP NF T Slide 9 But what is clinical reality? Not all patients with Amyloid burden clinically present with AD features Treatments focused on amyloid reduction do not change clinical picture Vascular component in AD pathology Autopsy Imaging Biological More mixed picture than believed 9 Slide 10 Impact of AD Global burden for those above age 60 years Disability years attributable to Dementia (11.2%) Stroke (9.5%) Musculoskeletal disease (8.9%) Cardiovascular disease (5%) All forms of cancer (2.4%) 10 Slide 11 Range (%)Median (%) Apathy40-8070% Hallucinations214928 Delusions107333 Agitationglobal109044 Agitationwandering05018 Verbal aggression115124 Physical aggression04614 Resistive/uncooperative276514 Behavioral Symptoms of AD Slide 12 Burden of BPSD 30% of the total annual costs of AD are invested in the direct management of BPSD Patients with behavioral symptoms need significantly greater formal, informal and total direct costs than those without the behavioral symptoms A difference up to $16,141/patient year Slide 13 Why prevent Approved meds for AD Modest benefit in cognitive domains Modest benefit in BPSD Typically slowing the worsening of symptoms only 6-12 months at best Prevention strategies also work for BPSD 13 Slide 14 14 Slide 15 Risk factors Age Risk for both AD and VaD doubling every five years after age 65 Apo E4 3-4 fold increase in AD Modifiable (50%) Diabetes HTN Obesity Inactivity Smoking Depression/PTSD/Apathy 15 Slide 16 When do we need to act? 16 Villemagne et al. Lancet 2013 Slide 17 Who to target? At-Risk population Genetic risk factors Apo E4 ABCA7 genotype Lipid homeostasis OR of 1.79 for African Americans Family history Washington University Wisconsin ADRC Behavioral risk factors Apathy Midlife risk factors Diabetes Obesity HTN Dyslipidemia 17 Reitz et al. JAMA; 2013: 309, 1483-92 Slide 18 Obesity Midlife BMI > 30: Doubled risk for AD in later life BMI 25-30: 35% increased risk Late life Weight loss often seen as risk for AD or early presentation of AD 18 Slide 19 Diabetes/Metabolic syndrome 2-5 fold increased risk of AD Adult children of AD patients Mean age 60 years Overwhelmingly white Brain effects of Insulin Resistance (HOMA-IR) Brain Volume: Reduced grey volume at baseline and greater atrophy over 4 years Cognitive function: IR associated with worse RAVLT learning Brain effects of metabolic syndrome Reduced CBF in frontal and parietal cortices Cognitive function: worse Immediate memory 19 Birdsill et al. (2013). Obesity, 21(7):1313-20 Willette et al. (2013). Diabetes Care, 36(2):443-9 Slide 20 Memory in Diabetes (MIND) Memory and Diabetes Study (ACCORD MIND) 40 months Intensive control of diabetes (Launer et al. Lancet Neurol. 2011; 10: 969-77) 52 clinical sites, 2977 patients, mean age 62.5 years No difference on Digit Symbol Substitution Test (DSST) Treatment group had bigger total brain volume (TBV) 20 Slide 21 Hypertension Midlife Increased risk of dementia in four longitudinal studies Associated with thinning of cortex High DBP was associated with increased amyloid deposition Latelife Inverse association 21 Slide 22 Treatment of HTN to prevent dementia Meta analysis of 19 randomized trials examining effect of antihypertensive therapy Benefit on Cognition Effect size 0.05 CI: 0.02-0.07 (Levi Marpillat et al. J. Hypertens 2013; 31: 1073-82) Reduce risk of all-cause dementia 9% 22 Slide 23 What are the benefits of changing lifestyle for those with genetic predisposition? ApoE4 + HTN RR for impaired cognition was 13 in individuals with HTN RR reduced to 2 with effective HTN treatment ApoE4 + HTN Increased amyloid deposition in poorly controlled HTN Reduced amyloid deposition in well controlled BP 23 Slide 24 Hyperlipidemia Midlife Increased risk of both AD and VaD Increased amyloid deposition Latelife Inverse 24 Slide 25 Multi-Vitamins Most commonly used dietary supplement in the United States taken by more than one-third of Americans vitamins C, E and beta-carotene may protect from oxidative damage B-vitamins the synthesis of neurotransmitters, DNA, and neuronal membrane, and prevent the accumulation of homocysteine, a risk factor for cognitive decline Vitamin A plays a role in neuronal survival and synaptic plasticity in the hippocampus 25 Slide 26 26 Slide 27 PHS II Randomized, double-blind, placebo-controlled 2222 factorial Beta-carotene, vitamin E, ascorbic acid, and a multivitamin Prevention of chronic diseases 14,641 male physicians aged 50 years A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary endpoint was a verbal memory score combining 4 tests of verbal memory, a strong predictor of Alzheimer disease. No difference in the mean cognitive change over time between the multivitamin and placebo groups No difference in the mean level of cognition at any of the four assessments 27 Slide 28 Behavioral problems PTSD Twice the rates of dementia Depression Apathy 28 Slide 29 Apathy The most common of the BPSD One of the earliest behavioral problem to appear in AD Perhaps the most persistent of all the behavioral problems Causes most disturbance to caregivers and Has the greatest impact on a patients function Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991; 3(3):243-254. Slide 30 Apathy as a behavioral marker Apathy is a behavioral marker for rapid progression of AD ApoE epsilon4 allele Greater neurofibrillary tangle burden in the anterior cingulate Faster progression of cognitive, and functional impairment Starkstein SE, Jorge R, Mizrahi R, Robinson RG. A prospective longitudinal study of apathy in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2006 Jan;77(1):8-11. Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL. Neuropathologic correlates of apathy in Alzheimer's disease. Dement Geriatr Cogn Disord. 2006;21(3):144-7. Slide 31 Apathy and conversion to dementia 7 times higher rates of conversion to dementia 131 patients with amnestic MCI Apathetic patients had an almost sevenfold risk of AD progression compared to amnestic-MCI patients without apathy (HR=6.9; 2.3-20.6) The risk of developing AD increased 30% per point on the NPI apathy item There was no increased risk of developing AD in amnestic-MCI patients with either a diagnosis or symptoms of depression. Palmer K, Di Iulio F, Varsi AE, Gianni W, Sancesario G, Caltagirone C, Spalletta G. Neuropsychiatric predictors of progression from amnestic-mild cognitive impairment to Alzheimer's disease: the role of depression and apathy. J Alzheimers Dis. 2010;20(1):175-83. Slide 32 Interventions that impact multiple risk factors 32 Slide 33 Education Marker of Cognitive reserve In a cohort of 500 patients with MCI, those with higher education were resistant to the harmful effects of WML on cognition Protection against clinical presentation of memory problems independent of CSF amyloid levels 33 Slide 34 34 Slide 35 Physical Activity: Four dimensions Duration (minutes/hours) Frequency (time per week/per month) Intensity (rate of energy expenditure) Circumstances or Purpose Slide 36 Current Recommendations for Physical Activity 150 minutes of moderate-intensity aerobic activity every week AND Muscle-strengthening activities on 2 or more days a week 75 minutes of vigorous-intensity aerobic activity every week AND Muscle-strengthening activities on 2 or more days a week Slide 37 Moderate-intensity Aerobic Activity Activity that increases breathing and heart rate Subjects will be able to talk while doing activity but not sing brisk walking lawn moving slow biking ballroom dancing tennis doubles general gardening Slide 38 Evidence for exercise Midlife physical activity Decreased risk of dementia 26 years later Decreased cardiovascular risk profile Reduction in brain tissue loss High and moderate physical activity Decreased risk of cognitive decline by 38% and 35% respectively Prospective study of Mediterranean diet and higher level of physical activity Protection against AD CAIDE Leisure time activity but not work related activity reduced risk of late life AD and dementia by 50% This effect was more pronounced in ApoE4 carriers 38 Slide 39 Physical activity for those at risk for AD Subjective memory complaints but no dementia 170 subjects randomized, 138 completed 18 month assessment 24 week home based physical activity program vs. usual care 150 min moderate intensity physical activity 3 sessions a week Walking, aerobic, strength training as chosen by participant Primary outcome was change in ADAS-Cog 39 Slide 40 Mean age 68.6 years Education 12 years participants in the intervention group improved 0.26 points (95% CI, 0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% CI, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the in- tervention and control groups was 1.3points (95% CI 2.38 to0.22) at the end of the intervention. At 18 months, participants in the intervention group im- proved 0.73points (95% CI 1.27 to 0.03)on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% CI 0.46 to 0.88). 40 Slide 41 Multimodal interventions 41 Slide 42 Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) 6077-year old CAIDE Dementia risk score (6 point or higher) CERAD neuropsychological test battery 2-year multi-domain intervention nutritional guidance cognitive training increased social activity monitoring and management of metabolic and vascular risk factors Primary outcome is cognitive decline measured by a sensitive Neuropsychological Test Battery the Stroop Trail Making tests. 42 Slide 43 Read each word: bluegreenblackgreen greenblueblueblack bluegreengreen red redredblueblue redblackredblack greengreenblackgreen redredgreenblue Slide 44 Say each color: XXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXX XXXX Slide 45 Disregard words, say each color: bluegreenblackgreen greenblueblueblack green redredredblu redblackredblack greenblackredblue Slide 46 Multidomain Alzheimer prevention study (MAPT) France 1680 70 years and above Multicenter, randomized, placebo controlled study Frail elderly people (defined by having subjective memory complaint, limitation in one IADL, slow walking speed) All participants sub grouped into 4 groups, 3 based on treatment options (omega 3 alone, multidomain intervention alone, both combined) and one placebo group 46 Slide 47 Prevention of dementia by intensive vascular care (preDIVA) Prevention of dementia by intensive vascular care Netherlands 3700 Non demented elderly from GP practices 7078 years Multisite, open, cluster randomized parallel group study every 4 month visit with practice nurse for life style and medical interventions, then 2,4 and final 6 years follow up 47 Slide 48 Healthy Aging Through Internet Counseling in the Elderly started January 2013 support management of vascular and life-style related risk factors in older adults, through an easily accessible Internet platform readily available nurse-support a randomized controlled clinical trial among 4600 elderly is planned (starting 2015) 48 Slide 49 Case Vienna Transdanube Aging (VITA) Study 76 yr woman MMSE 29 and high scores on tests 81 yr MMSE 25 Episodic memory tests declined by two standard deviations MRI: medial temporal lobe atrophy worsened Temporal cortical atrophy Probable AD diagnosis given 49 Slide 50 MRI 50 Slide 51 Were they right to give the diagnosis? Yes 51 Slide 52 What happened next? She changed lifestyle Started writing a diary and eventually published it Restarted playing the accordion Meeting friends and relatives Daily walking and gardening Reading books and newspapers 30 months later 83.6 yrs old MMSE 29/30 MRI: Increasing mesial temporal lobe atrophy 52 Slide 53 53 Slide 54 What are we doing currently at the GRECC? rTMS for Apathy In MCI (UAMS TRI) In AD (VISN 16 pilot) Improving function, quality of life, glycemia in diabetics with dementia Alzheimers Association Data analysis Slide 55 Geriatric Walking Clinic Technology to Improve Motivation for Exercise (TIME) Funding Sources: The Office of Rural Health Slide 56 Wii-Fit Alzheimers Study 56 Slide 57 Wii-Fit vs. Mind-Fit in Elderly 57 Slide 58 Take away points Dementia is a potentially preventable disease Life style risk factors contribute to approximately 50% risk of dementia Prevention interventions need to start early Multimodality interventions including physical activity may be helpful in reducing risk for dementia